At least two billion people suffer from helminth infections globally, the majority of whom reside in the developing world. Helminths differ from viruses, bacteria and protists in that they exhibit complex life cycles, often involving multiple developmental pathways that result in different phenotypic outcomes. Developmental decisions are believed to be influenced by host factors and provide the parasite with a means to respond to changing conditions within the host. The broad objectives of this proposal are to develop a molecular understanding of the signals and receptors involved in these interactions, using a murine model of schistosome infection. This knowledge should reveal new opportunities to disrupt helminth life cycles for therapeutic and prophylactic purposes. Trematodes of the genus Schistosoma, which affect 200 million people worldwide, constitute a useful and important laboratory model of pathogenic helminths. Studies involving S. mansoni have demonstrated that initiation of normal development within the mammalian host is dependent on the receipt of appropriate host signals by the parasite. Hepatic CD4+ T cells play a central role in delivering this signals to the developing worm. Further, an intimate physical interaction occurs between CD4+ T cells and developing schistosomes. Specific aim 1 of this proposal it to identify the host molecules responsible for modulating schistosome development. Candidate molecules produced by hepatic CD4+ T cells will be systematically identified using array technology and supporting molecular techniques. Suitable candidates will then be tested for modulatory activity in vivo, using genetically altered mice, and in vitro, using a developing parasite culture system. Specific aim 2 proposes to identify schistosome molecules that participate in the physical interaction with CD4+ T cells by employing a signal sequence trap library screening approach. Specific aim 3 is to identify the molecular differences in gene transcription that underlie the obvious phenotypic differences between normal parasites from wild type mice and attenuated parasites from immunodeficient animals. This specific aim will make use of emerging array technology and supporting molecular techniques to identify genes that are differentially expressed in the two phenotypic states of the parasite. Identified genes will provide valuable molecular markers of parasite development for use in subsequent studies. [unreadable] [unreadable]